SUMMARY ABSTRACT In both humans and laboratory animals, quantitative measures of intelligence are predicted by a) the expression of the dopamine Drd1a and related genes in the prefrontal cortex (PFC; Kolata et al., 2010), and b) by the affinity of the D1 receptor to dopamine in the medial and dorsolateral PFC (Klingberg & McNab, 2009; Wass et al., 2013. Relatedly, working memory training promotes improvements in intelligence that coincide with increases in the affinity of the D1 receptor in the PFC (McNab et al., 2009; Wass et al., 2013). Despite the increase in Drd1a gene expression and the increased affinity/sensitivity of the D1 receptors in subregions of the PFC that are associated with higher cognitive abilities, membrane-bound D1 receptors are not differentially expressed as a function of animals' cognitive abilities (Wass et al., 2010). In combination with the above results, this latter observation suggests that a sub-membrane level influence on the trafficking of (sequestered) D1 receptors differentially regulates the availability of these receptors across animals that exhibit variations in general cognitive performance. This hypothesis suggests that the pool of immature D1 receptors available to meet the demands of cognitive challenges may underlie (at least in part) variations in ?intelligence?, and may be available to respond to cognitive demands (e.g., working memory training). The elucidation of this dynamic process will not only aid in our understanding of intelligence, but will help to establish a framework with which to promote improvements in general cognitive performance. The dopamine receptor interacting protein, DRiP78, binds to the immature D1 receptor and sequesters the receptor in the endoplasmic reticulum (ER). The DRiP78 binding cite is shared by antibodies to the D1 protein, and thus renders the receptor undetectable to these antibodies (and thus may account for our inability to detect increases in receptor expression). We will determine whether a correlation exists between animals' general cognitive ability and the expression of DRiP78, with the goal of determining whether an undetectable pool of immature receptors resides in the ER of animals of high cognitive abilities. Relatedly, we will determine if animals of higher general cognitive ability exhibit an increase in the rate of D1 receptor turnover (which would potentiate the receptor's affinity to dopamine). Lastly, we will determine if the rate of receptor turnover and/or membrane-bound receptors is elevated as a consequence of high cognitive demands (such as during working memory training), and whether the degree of elevation is predicted by animals' innate cognitive ability. Consistent with the R03 Program, this is a tightly-focused series of experiments that will clarify our understanding of the instantiation and malleability of general cognitive performance. These experiments will elucidate a biological basis for the interaction between environmental experience and the genome in the regulation of individual differences in general cognitive abilities, and are preliminary to the development of molecular/pharmacological and behavioral strategies to promote improvements in general cognitive abilities.